Emulsions are colloidal systems which have application in many industrial products such as food, cosmetics and pharmaceuticals. Oil-in-water emulsions are made of oil droplets which are dispersed in an aqueous continuous phase. One of the uses of emulsions in industry is to deliver active ingredients and components, such as, flavours, colours, vitamins, antioxidants, anti-microbials, pesticides, herbicides, cosmetics, nutraceuticals, phytochemicals and pharmaceuticals.
The active components can be oil soluble or water soluble, although their solubility in these environments can vary from highly soluble to poorly soluble. Administering active components that are not soluble in water poses a challenge as it requires the use of an appropriate vehicle for bringing an effective amount of the active component into the desired place of action. Oil-in-water emulsions are commonly used for the delivery of active components that are not soluble in water. Active components that are soluble in oil are dissolved/dispersed within the oil phase of the emulsion. Active components that are poorly soluble in both oil and water can be incorporated as part of the interfacial region of the oil-in-water emulsion.
The emulsions that are conventionally used to deliver active components suffer from a number of significant limitations and disadvantages. Emulsions are kinetically stable structures that are subject to destabilisation through a number of mechanisms, ultimately resulting in complete phase separation of the emulsion. The tendency of emulsions to physically alter over time presents problems for their storage and handling. Furthermore this physical degradation increases the likelihood that the preparation is in a sub-optimal state when physically administered.
The size (diameter) of a conventional oil-in-water emulsion ranges from several hundred nanometers to several microns. Since these particles are in the order of or greater than the wavelength of light they have an opague appearance. This has the disadvantage of altering the optical clarity of any product that the emulsion is incorporated into, reducing visual appeal. Furthermore, emulsions of this size have a low interfacial area to volume ratio. This has a negative impact on the emulsions ability to dissolve poorly soluble bioactives which are soluble at an interface. The amount of a poorly soluble bioactive that can be dissolved at an interface being directly linked to the relative amount of interfacial area.
Another disadvantage of using conventional oil-in-water triglyceride emulsions to deliver active ingredients is that upon oral ingestion the release of the active ingredient is dependant on the rate and extent of lipolysis. Whilst such emulsions are capable of transporting active ingredients through the aqueous environment of the gastrointestinal tract, the ultimate release of the emulsified active ingredient is dependant on emulsion digestion. The rate of triglyceride emulsion digestion is a function of many factors, pH, co-lipase/lipase concentration, bile salt and emulsion surface area. Principle amongst them is the relative ratio of emulsion interfacial area to its volume. Emulsions with higher surface area to volume ratios undergo much faster lipolysis than those with low surface area to volume ratios.
When an emulsion has a particle size of less than 100 nm, the emulsion has the added benefit of becoming translucent or even transparent. The formation of very small (sub 100 nm) emulsions has the added benefit of increasing the relative amount of interfacial area considerably. An increase in the relative amount of interfacial area can lead to a greater ability to dissolve/disperse poorly soluble active components at the interface. Furthermore, an increase in the relative amount of interfacial area can lead to a faster rate of digestion by lipolysis compared to conventional oil-in-water emulsions. A faster rate of lipolysis can lead to a more rapid release of the emulsified active ingredient.
Two classes of emulsion that can have a particle size less than 100 nm are microemulsions or nanoemulsions. These two classes of emulsion are fundamentally different.
A microemulsion is an emulsion which forms spontaneously as a result of the ultralow interfacial tension and the favourable energy of structure formation. Microemulsions are thermodynamically stable having particle sizes that do not change with time. One disadvantage of a microemulsion is that it may become physically unstable if its composition is changed, e.g. upon dilution, acidification or heating. The spontaneous formation of a microemulsion arises from the synergistic interaction of surfactant, co-surfactant and co-solvent to effectively “solubilise” oil molecules. As a result it is known that a disadvantage of microemulsions is that they contain a high amount of surfactant relative to the amount of oil. In the case of foods, many surfactants have a bitter taste. Furthermore WHO and the FDA have placed restrictions on the daily intakes of many of these surfactants.
A nanoemulsion is an emulsion which does not form spontaneously, but is instead formed by the application of shear to a mixture of oil, water and surfactant. Unlike microemulsions, nanoemulsions are kinetically stable and their particle size may increase over time via coalescence, flocculation and/or Ostwald ripening. The very small size of nanoemulsions makes them particularly prone to particle size growth by Ostwald ripening. An increase in emulsion particle size over time is disadvantageous as the emulsion will lose its clarity accompanied with a corresponding increase surface area.
Like microemulsions, nanoemulsions can have the benefit of appearing translucent/transparent as a result of their small size. Also, like microemulsions, nanoemulsions have the benefit of having a high interfacial area to volume ratio which can aid in the dissolution of poorly soluble bioactives and aid the rapid digestion of the emulsion by faster rates of lipolysis. Furthermore, unlike many microemulsions, nanoemulsions retain their structure (small size) upon dilution and/or acidification. This may have the added benefit of aiding active adsorption as it is currently thought that emulsions below 100 nm have a greater ability to penetrate epithelial layers such as the skin and oral mucosa. Another advantage of nanoemulsions is that their creation requires the use of a significantly lower amount of surfactant compared to microemulsions. This gives the nanoemulsions the advantage that less surfactant is incorporated upon addition of a certain amount of active/oil. This is beneficial from a toxicological, regulatory and taste perspective.
The nature of the oil contained within the nanoemulsion is also important. It is advantageous to have an oil that is a triglyceride as they present a lower toxicological and/or irrigational profile to humans than synthetic or hydrocarbon oils. There are three classes of triglycerides, short chain triglycerides (less than 6 carbons in fatty acid chain), medium chain triglycerides (6 to 12 carbons in fatty acid chain) and long chain triglycerides (greater than 12 carbons in fatty acid chain). It is advantageous if the triglyceride oil within a nanoemulsion is of a long chain format, with preferably some degree of unsaturation as these oils have been shown to provide positive nutritional benefits and are considerably more stable against Ostwald ripening.
The creation of nanoemulsions and/or nanodispersions using medium chain triglycerides, especially miglyol 812, is known. Medium chain triglycerides are used as their smaller molecular bulk and higher solubility in water aids their ability to form nanoemulsions and/or nanodispersions. In contrast, it is known that the large molecular bulk of long chain triglycerides prevents them from readily forming clear microemulsions or nanoemulsions.
There remains the challenge of creating a nanoemulsion whose oil phase contains a long chain triglyceride where the emulsion has an intensity average size of less than 100 nm, high stability against Ostwald ripening and lower relative amounts of surfactant. The creation of such a nanoemulsion would be advantageous as it will increase product stability and clarity, improve the solubility of some poorly soluble actives and improve organoleptic properties.